Artemisinin Combination Therapy (ACT), Artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), the first-line treatments for uncomplicated malaria in most endemic regions, remove the vast majority of the malaria parasites, and rapidly alleviates symptoms. Multiple lines of evidence have shown that significant decline in human malaria mortality rates and prevalence in recent years can be attributed in part to the use of ACT. Recently emerging resistance to ACT will however challenge malaria control and eradication efforts. We have shown in an ongoing series of studies that bumped kinase inhibitors? (BKIs) including lead 1553 inhibit Plasmodia CDPK4 and prevent exflagellation of male gametocytes. BKIs inhibit malaria parasites invasion of Anopheles stephensi midgut and development of infective sporozoites. Using chemical-genetic methods, we have confirmed that BKIs block malaria transmission via inhibition of CDPK4 and do not inhibit mammalian kinases. Lastly, we have evidence of low oral clearances and long systemic half-lives of BKI-1553 in mice, rats, sheep, calves, dogs and monkeys, with good exposure for >14 days needed for effective transmission blocking without measurable toxicity. This research proposal capitalizes on the unique preliminary biochemical, phenotypic and pharmacokinetic findings to hypothesize that co-formulation of these transmission-blocking BKIs with AL and DP could stop transmission of artemisinin-resistant malaria strains with Specific Aim 1. Determine optimum BKI, AL and DP dose combination for efficacy studies in which we will obtain critical information needed for selecting optimum doses for BKI partners and AL or DP in subsequent animal model of malaria. Priority will be given to 1553 because of its extensive PK/PD proficiency and favorable exflagellation profiles while additional compounds will be made ready to advance as backups. In Specific Aim 2 we will test BKI-ACT combinations for efficacy studies in animal models. BKI 1553 will be tested in combinations with AL and DP for efficacy studies in rodent infection models against blood stage malaria parasites and mosquito transmission. Relevant PK data will be collected for adjusting, modifying and optimizing the effective dose to achieve complete parasite clearance and transmission blocking with no toxic side effects. BKI-ACT combinations that meet an activity threshold (generally 100% clearance of blood stage parasite and <15% mean oocyst infectivity rate for >14 days after treatment) will undergo follow up safety studies. Additional assays will be carried out to assess the direct impact of transmission blocking BKI-ACT in reducing the prevalence of artemisinin resistance and the elimination of malaria in an infected rodent colony. Our primary goal is to develop an oral agent to be administered with AL and DP malaria therapy. In the end, we expect to have developed one to 2 leads that will be advance to preclinical studies as an adjuvant drug to AL and DP.